In this investigation, we examined plasma 25-OH-D among patients diagnosed with EOSPE who either had SGA or normal growth. EOSPE is one of the most serious forms of hypertensive disease in pregnancy.12
This study found significantly lower maternal levels of 25-OH-D among patients with an SGA fetus relative to those with normal growth. Furthermore, there was a significant correlation between 25-OH-D and percentile growth suggesting a possible underlying mechanistic role for vitamin D in fetal growth that is likely mediated through actions in the placenta.5
This is the first report of a significant relationship between maternal vitamin D level and fetal growth. As this investigation focused on the most severely affected patients with preeclampsia, future clinical trials may focus on the possible impact of Vitamin D deficiency or supplementation upon fetal growth outcomes in preeclamptic and normal pregnancies.10, 12
Understanding the mechanisms behind fetal growth are complex and interventions to improve growth in conditions known to be at high risk for SGA are poorly understood.15–17
Vitamin D has been implicated in providing critical signals in gene regulation and expression in early placental development among placental trophoblast models.18–22
As the placenta has all of the necessary molecular machinery to convert 25-OH-D to the active form of vitamin D (1,25-OH2
), it has been suggested that the placenta may convert the storage form (25-OH-D) to the active form of vitamin D for local or paracrine utilization.5, 18
has been shown to improve endothelial function among patients on renal hemodialysis through a possible paracrine action.23–24
In endothelial cells, 1,25-OH2
has been demonstrated to increase expression of vascular endothelial growth factor (VEGF), a potent proangiogenic protein known to be diminished in preeclampsia) through binding to vitamin D receptor and co-localization to a vitamin D responsive element in the VEGF promoter.25
If this mechanism is also demonstrated in the placental trophoblast, it is possible that inadequate vitamin D levels may affect both preeclampsia and fetal growth through alterations in VEGF activity.
We have previously published data associating low maternal 25-OH-D levels with the diagnosis of EOSPE.7
In vitamin D deficiency, it is possible that the lack of these signals may play a critical role in Stage I of placental development that leads to the ultimate recognition of Stage II and a diagnosis of preeclampsia.19, 22, 26
It is not precisely known how these signals might lead to the ultimate diagnosis of preeclampsia, and thus, epidemiological observations of the incidence of preeclampsia associated with vitamin D deficiency currently lack fully defined pathways through which biomolecular mechanisms explain this relationship. However, based on the observations of this and other studies linking vitamin D deficiency and preeclampsia, vitamin D supplementation remains a possible intervention and possible improved pregnancy outcomes through prevention or delay of preeclampsia or improved fetal growth in pregnancies at high risk for preeclampsia.7–9
This study has important limitations that should be noted and addressed in future investigations. Since these patients were enrolled at the time of diagnosis of EOSPE, an assessment of preconception and early pregnancy dietary intake, sun exposure, or maternal baseline 25-OH-D was not available to help understand the impact of these factors on the development of EOSPE. It is also important to recognize that this investigation cannot stand alone to assert a role for vitamin D supplementation in pregnancy to improve pregnancy outcomes. A recent investigation noted that maternal, first trimester, free 25-OH-D levels were not associated with first trimester blood pressure or later development of preeclampsia among 170 patients where 39 subsequently developed preeclampsia. However, this investigation was limited by a small sample size and primary analysis of term preeclampsia. As EOSPE is known to have a more significant impact on maternal and fetal outcomes, this investigation may not be comparable to those where term preeclampsia is considered in possible association with maternal 25-OH-D.27
However, this study does provide additional evidence suggesting the need for prospective longitudinal studies or randomized controlled trials of vitamin D supplementation examining the potential for impact on adverse pregnancy outcomes.